P1237: HSF1 PROMOTES CHEMORESISTANCE IN DIFFUSE LARGE B-CELL LYMPHOMA VIA A PRMT5-DEPENDENT TRANSCRIPTIONAL PROGRAM HSF1通过PRMT5依赖性转录程序促进弥漫性大B细胞淋巴瘤的化疗耐药性
Authors: Qingqing Cai, Yu Fang, Xu Chen, Ming Huang, Yuchen Zhang, Xiaopeng Tian, Huiqiang Huang, Yi Xia
Journal: HemaSphere (2023)

Topic: 20. Lymphoma Biology & Translational Research Background: Diffuse large B-cell lymphoma (DLBCL) is characterized by heterogeneous clinical course and biological process. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) is the standard treatment for DLBCL in the frontline setting. However, about 15% of the patients treated with R-CHOP have refractory disease and 20-25% of the patients relapse after remission. Therefore, it is of great importance to explore new prognostic biomarkers and therapeutic targets for DLBCL patients. Heat shock factor 1 (HSF1) is a transcription factor that mediates cellular stress response and participates in the proliferation and invasion of a variety of malignant tumors by regulating the transcription of a group of oncogenes Aims: We conducted this study to analyze the correlation between the expression of HSF1 and first-line treatment sensitivity and survival prognosis of DLBCL patients; and explore the biological function and mechanism of HSF1 in DLBCL, in order to identify novel prognostic biomarkers and potential therapeutic targets for DLBCL. Methods: Immunohistochemistry was carried out to detect the expression of HSF1 in DLBCL and elucidate the association of HSF1 with first-line treatment sensitivity and survival prognosis. Proliferation, cell cycle, immunohistochemistry and subcutaneous tumor formation model in NOD-SCID mice were performed to evaluate the function of HSF1 and its inhibitor, DTHIB, in DLBCL cells in vitro and in vivo. The downstream target genes regulated by HSF1 were identified by transcriptome sequencing and confirmed by qRT-PCR and Western Blot. The regulation mechanism was verified by Co-IP and ChIP-qPCR Results: The high expression of HSF1 was significantly associated with inferior first-line treatment sensitivity (Figure 1A-B), and poor progression-free survival (PFS, HR,1.71; 95%CI, 1.14-2.56; P=0.008; Figure 1C) and overall survival (HR, 1.69; 95%CI, 1.01-2.83; P=0.045; Figure 1D) of DLBCL patients. HSF1 was an independent predictor of poor PFS in DLBCL patients (HR, 1.56; 95%CI, 0.97-2.51; P=0.049). Knockdown of HSF1 or using DTHIB significantly decreased the proliferation, arrested the cell cycle at G1 phase and increased the sensitivity of vincristine and doxorubicin in DLBCL. Mechanical study showed that both knockdown of HSF1 and using DTHIB could significantly decrease the expression of genes related to cell cycle, DNA damage repair and p53 signaling pathway (Figure 1E-F). Further studies demonstrated that HSF1 could interact with PRMT5 and enrich in the promoter region of the downstream genes of the above pathways, thus regulating their expression and ultimately mediating a variety of biological functions of DLBCL. Summary/Conclusion: These data demonstrated that high expression of HSF1 is associated with inferior sensitivity to first-line chemotherapy and poor prognosis of DLBCL patients. HSF1 could interact with PRMT5 and regulate the downstream genes, and consequently promote cell proliferation and increase resistance to vincristine and doxorubicin. Therefore, our findings suggest that HSF1 is a promising prognostic biomarker and therapeutic target of DLBCL.Keywords: Chemoresistance, Diffuse large B cell lymphoma